期刊
JOURNAL OF PHYSICAL CHEMISTRY B
卷 115, 期 20, 页码 6764-6775出版社
AMER CHEMICAL SOC
DOI: 10.1021/jp202079e
关键词
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资金
- Spanish Ministry Ministerio de Ciencia e Inovacion [CTQ2009-14541-C2]
- Universitat Jaume I - BANCAIXA Foundation [P1 . 1B2008-36, P1 . 1B2008-37, P1 . 1B2008-38]
- Generalitat Valenciana [Prometeo/2009/053]
- SEUI [PHB2005-0091-PC]
- CAPES
- Spanish Ministry Ministerio de Educacion [PR2009-0539]
O-Glycoprotein 2-acetamino-2-deoxy-beta-D-glucopyranosidase (O-GlcNAcase) hydrolyzes O-linked 2-acetamido-2-deoxy-beta-D-glucopyranoside (O-GlcNAc) residues from post-translationally modified serine/threonine residues of nucleocytoplasmic protein. The chemical process involves substrate-assisted catalysis, where two aspaitate residues have been identified as the two key catalytic residues of O-GlcNAcase. In this report, the first step of the catalytic mechanism used by O-GlcNAcase involving substrate-assisted catalysis has been studied using a hybrid quantum mechanical/molecular mechanical (QM/MM) Molecular Dynamics (MD) calculations. The free energy profile shows that the formation of the oxazoline intermediate in the O-GlcNAcase catalytic reaction takes place by means of a stepwise mechanism. The first step would be a cyclization of the acetomide group, which seems to be dependent on the proton transfer from a conserved aspartate, Asp298 in Clostridium perfringens O-GlcNAcase. From this new intermediate, a proton is transferred from the azoline ring to another conserved aspartate (Asp297) thus forming the oxazoline ion and departure of the aglycone. In addition, averaged values of protein-substrate interaction energy along the reaction path shows that, in fact, the transition states present the highest binding affinities. A deeper analysis of the binding contribution of the individual residues shows that Asp297, Asp298, and Asp401 are basically responsible of the stabilization of these complexes. These results would explain why O-(2-acetamido-2deoxy-D-glucopyranosylidene)amino-N-phenycarbamate (PUGNAc), 1,2-dideoxy-2'-methyl-alpha-D-glucopyranoso-[2,1-d]-Delta 2'-thiazoline (NAG-thiazoline), and GIcNAcstatin derivatives are potent inhibitors of this enzyme, resembling the two transition states of the O-GlcNAcase catalytic reaction path. These results may be useful to rational design compounds with more interesting inhibitory activity.
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